Over the years, the use of coatings for medical devices and drug delivery has become a necessity, notably for augmenting the capabilities of medical devices and implants. Drug eluting medical device coatings have emerged as a leading biomedical device for the treatment of cardiovascular disease.
Heart disease and heart failure are two of the most prevalent health conditions in the US and the World. In coronary artery disease, the blood vessels on the heart become narrow. When this happens, the oxygen supply is reduced to the heart muscle. The primary cause of coronary artery disease is fat deposits blocking the arteries (“plaque”). The treatment of coronary artery disease has been initially done by surgery and CABG (Coronary Artery Bypass Graft), which are normal and efficient procedures done by cardiac surgeon. The mortality and morbidity, however, were high. In the 60's, some physicians developed a low invasive treatment by using medical devices. By going through a small incision at the femoral artery, they were able to treat the disease: balloon angioplasty (used to widen an artery that has become narrowed using a balloon catheter which is inflated to open the artery. PTCA=Percutaneous Transluminal Coronary Angioplasty) is used in patients with coronary artery disease. Following balloon angioplasty, approximately 40 to 50% of coronaries arteries are affected by restenosis (the re-narrowing of a blood vessel after it has been opened, usually by balloon angioplasty) within 3 to 6 months due to either thrombosis (the development of a blood clot in the vessels which may clog a blood vessel and stop the flow of blood) or abnormal tissue growth. As a result, restenosis constitutes the major limitation to the effectiveness of the PTCA.
The introduction of the Bare Metal Stent (BMS), in the late 80's, used to keep coronary arteries expanded, went some way towards alleviating this problem, as well as that of the dissections of arteries upon balloon inflation in the PTCA procedure. The stent is mesh tube mounted on a balloon catheter (a long thin flexible tube that can be inserted into the body; in this case, it is threaded to the heart). But the BMS continues to be associated with a restenosis rate of around 25% of patients affected 6 months after stent insertion: stent struts end up embedded by the arterial tissue in growth. This tissue is essentially made of smooth muscle cells (SMC's), the proliferation of which is provoked by the initial damaging of the artery upon stent apposition. The apposition indeed destroys the layer of endothelial cells (EC's) which have to further proliferate and migrate in order to recolonize the stent struts over the SMC's in order to stop their proliferation.
The Biomed industry partly solved this failure rate by designing a new generation of stents providing a coating able to release selected drugs (Sirolimus, Paclitaxel, ABT578, Tacrolimus, Everolimus . . . ) in the vessel walls, in order to prevent restenosis. The Drug Eluting Stent (DES) attracted increasing attention during the late 90's as potentially offering a more effective way to lower the rate of restenosis to a single figure. Ideally, the drug should prevent the proliferation of the SMC's while allowing early recolonization by active EC's, as the latter cells spontaneously produce nitrogen oxide (NO), a small molecule acting as a signal to stop the proliferation of SMC's.
Most DES on the market are made on the basis of a polymeric release matrix from which the drug is eluted. The polymer is so called biostable: the polymer stays permanently on the stent, and is thus assumed to have little effect both on the inflammatory response and the recolonization by EC's. The main drawback of these DES is that they cannot release 100% of the drug they host. One significant consequence of this is that the recolonization process is hindered by the drug remaining in the coating (as most of the drugs “kill” EC's equally or more efficiently than SMC's). This drawback has potentially lethal and dramatic consequences for the patients and thus, for the DES industry. Indeed, despite the fact that restenosis could be lowered down from ca. 20% with BMS to ca. 5% with DES, the industry is presently facing a major challenge revealed and unsolved by the current DES: the phenomenon of late thrombosis, i.e. re-clotting of the artery one year or more after stent implantation.
It has long been known that the implantation of bare metal stents was also the source of thrombosis, in addition to restenosis, but that the former could be easily coped with by a systemic bi-therapy associating two anti-thrombotic agents, typically aspirin and clopidogrel (Plavix®). Typically, patients to whom a stent was opposed were thus prescribed such a bi-therapy for 1 to 2 months. Follow-up data have long pointed out the excellent results of this combination as regards thrombosis. With drug eluting stents, numerous cases of re-clotting of the artery due to coagulation (thrombosis) soon after the interruption of the bi-therapy have been reported, which pushed cardiologists to maintain the bi-therapy for 3, 6, 9 and now 12 months or more. Several cases were reported that myocardial infarction with total stent thrombosis may occur only a couple of weeks after interruption of a 18 month bi-therapy.
Late thrombosis is an abrupt complication which can be lethal when occurring if the patient is not under medical follow-up or—even if he is—while the patient is away from the cathlab or from an adequately equipped medical centre. Moreover, bi-therapy is a very uncomfortable bottleneck, as some patients either decide by themselves to stop it after a period they estimate as long, or may forget to have their medicines, or may have to undergo a clinical intervention which could not be anticipated, and are thus in the position to have to stop the anti-thrombotic treatment.
The exact reasons accounting for the phenomenon of late thrombosis are still incompletely understood. Pathologists estimate that the late thrombosis issue reveals an incomplete recolonization of the stent by EC's, leaving metallic or polymeric materials in contact with the blood over prolonged periods, on which platelet adhesion is likely to occur and lead to catastrophic precipitation of a thrombus. Alternate interpretations have emerged which claim that the incomplete recolonization by EC's is the result of the incomplete release of the drug from the release layer, which “kills” migrating EC's in their attempt to migrate and proliferate on the surface of said polymer+drug layer.
Thus, risks of late thrombosis are a severe drawback of existing DES.
Due to the very high mechanical constraints a stent is facing during its manufacturing process (crimping on the balloon), during its travel in the artery (especially over calcified lesions) and during its expansion (the diameter of the stent is increased by a factor of 3 to 5), uncontrolled crackings and delaminations are often the rule. Crackings and delaminations may provoke an artificial “roughness” which ranges from a few tens of microns to several millimeters, and which is thus prone to seriously hinder the proper recolonization of the stent by EC's.
However “roughness” alone cannot account alone for hinders of recolonization by EC's. A study evaluating the recolonization by EC's obtained at 28 days in pig arteries with two overlapping Cypher® or two Taxus® stents in the same artery, as compared to their respective bare metal counterparts, i.e. two Bx Velocity® or two Express® in the same artery, respectively, evidence that:                even though the “roughness” of the surface to be recolonized is fairly high with both the DES and the BMS (because of the overlap between the two stents), the recolonization is always better with the BMS as compared to the DES;        whatever the DES, Cypher® or Taxus®, i.e. whatever the drug which is being released, the recolonization is always better with the corresponding BMS.        
This result strongly suggests that, aside of the “roughness” of the coating and of the stent surface after deployment, recolonization is always superior in the absence of drug. This is to be correlated with the fact that:                all existing DES have a biostable layer. The release of the drug is obtained by pure diffusion, and thus can never be complete: there is always some drug left in the coating to be recolonized over prolonged periods;        all drugs in use in existing DES (Sirolimus, Paclitaxel) have a threshold toxic concentration which is comparable or even lower against EC's as compared to SMC's, i.e. they can “kill” EC's equally well or even better than SMC's.        
This points to a severe drawback of existing DES in that they locally maintain drugs which are toxic to the EC's over prolonged periods.
Last but not least, these drugs may have an effect on the remodelling of the artery. It was noted a so called “stent malaposition” showing that some of the stet struts were incompletely in contact with the walls of the arteries. It is believed that most stent malapositions are due to the effect of the drug, especially in the case of Sirolimus, which provokes a so called “positive remodelling” of the artery, i.e. its progressive overdilatation: the stent is initially well in contact with the artery walls, but eventually “floats” within the artery which diameter increases under the effect of the drug. In such a case, some of the stent struts remain non recolonized by EC's (as they are too far away from the artery wall) and can be the source of a thrombosis stemming from the direct contact of the polymer material with the blood. Such a thrombosis may not appear as long as the patient is under anti-platelet bi-therapy, but soon starts right after the bi-therapy is interrupted (late thrombosis). This, again, points to the severe drawback of existing drug eluting stents due to the prolonged stay of the drug on the surface of the stent.